美国加州大学旧金山分校王磊、南方医科大学徐洋、中国科学院理化技术研究所王谦等研究人员合作开发出一个新型共价蛋白药物平台。该研究于2020年6月23日在线发表于国际学术期刊《细胞》。

Title: Developing Covalent Protein Drugs via Proximity-Enabled Reactive Therapeutics

Author: Qingke Li, Qu Chen, Paul C. Klauser, Mengyuan Li, Feng Zheng, Nanxi Wang, Xiaoying Li, Qianbing Zhang, Xuemei Fu, Qian Wang, Yang Xu, Lei Wang

Issue&Volume: 2020-06-23

Abstract: Small molecule covalent drugs provide desirable therapeutic properties over noncovalent ones for treating challenging diseases. The potential of covalent protein drugs, however, remains unexplored due to protein’s inability to bind targets covalently. We report a proximity-enabled reactive therapeutics (PERx) approach to generate covalent protein drugs. Through genetic code expansion, a latent bioreactive amino acid fluorosulfate-L-tyrosine (FSY) was incorporated into human programmed cell death protein-1 (PD-1). Only when PD-1 interacts with PD-L1 did the FSY react with a proximal histidine of PD-L1 selectively, enabling irreversible binding of PD-1 to only PD-L1 in vitro and in vivo. When administrated in immune-humanized mice, the covalent PD-1(FSY) exhibited strikingly more potent antitumor effect over the noncovalent wild-type PD-1, attaining therapeutic efficacy equivalent or superior to anti-PD-L1 antibody. PERx should provide a general platform technology for converting various interacting proteins into covalent binders, achieving specific covalent protein targeting for biological studies and therapeutic capability unattainable with conventional noncovalent protein drugs.

DOI: 10.1016/j.cell.2020.05.028

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30623-1